Morphine addiction: Enzyme activity

Ezine

Published: May 16, 2017

Author: Steve Down

Channels: Proteomics & Genomics / Proteomics

Morphine dependency

Morphine is one of the best drugs for acute pain treatment and is a mainstay of the medical profession. However, its use is limited by severe side effects which include anxiety, depression reduced heart rate and hallucinations. In the long term, continued morphine use allows the human body to develop tolerance so that larger doses are required to maintain the painkilling properties, which contributes to the risk of dependency. Morphine, like other opiates, is a highly addictive drug.

Many research groups have examined the molecular basis behind the pharmacological action of morphine. A number of these studies have involved proteomics and highlighted various proteins that had their abundances altered as a result of morphine treatment. But, as Piotr Suder and colleagues from AGH University of Science and Technology, Cracow, have pointed out, changing levels do not necessarily indicate a change in activity. So, they decided to take a closer look at the correlation between protein abundances and activities to provide more information on the mode of action of morphine.

In 2010, their group created the Morphinome Database which contains 1100 unique proteins that have been reported to be regulated by morphine administration. Now, they selected four candidate proteins from the database, to look for changes in activity. Discovering more about the molecular mechanism of morphine could lead to safer and more potent painkilling drugs as well as provide the potential to treat opiate addiction.

Enzyme activities

The proteins were pyruvate kinase (PK), malate dehydrogenase, NADH dehydrogenase (also known as Complex I) and ATP synthase (Complex V), all of them being implicated from the results of more than one independent study. There is no overall agreement in the literature about their regulation in the brain after morphine administration but they were selected because they have all been associated with energy metabolism, a pathway that has been neglected in addiction processes for morphine and other drugs.

The experiments were conducted on rats which were dosed with morphine for 14 days to create dependency. A second group was treated this way then deprived of morphine for 7 days to produce withdrawal and a third group was treated with saline as controls.

After being sacrificed, the mitochondrial fractions of the rat brains from each group were collected and analysed using commercial enzyme activity assay kits for each of the four enzymes. This approach would reveal any global influences of morphine on brain metabolism, rather than pinpointing particular brain regions.

Pyruvate kinase has potential

Of the four proteins, only PK displayed any alterations in activity, decreasing during morphine administration then rising during withdrawal. A similar pattern has been reported for the enzyme adenylyl cyclase which has been taken to reflect a cellular response to drug dependency, so the same could be attributed to PK. However, the researchers point out that there may be other factors influencing cellular metabolism that involve opioid receptors in the brain.

The failure to capture any activity changes for the remaining three enzymes could be caused by the complexity of reactions that occur in the brain but, again, the team are at pains to point out that changes in protein abundances do not necessarily affect brain metabolism.

Despite this caution, this type of research could prove valuable for developing new ways to alleviate pain and develop novel therapies to treat morphine addiction. Once the mechanisms that control and regulate enzyme activity following morphine administration are uncovered, new therapeutic targets will become evident and safer analgesics could be on the horizon.